Positron emission tomography (PET) studies of beta-amyloid deposition (A[unreadable]) have demonstrated A[unreadable] in vivo in Alzheimer's disease (AD) and an association between A[unreadable] and subsequent cognitive decline in normal elderly and mild cognitive impairment subjects (MCI). However, progression of cognitive deficits is associated with only modest increases in A[unreadable] and substantial, progressive alterations of brain structure (volumetric changes measured on Magnetic Resonance (MR) scans) and function (PET scans of regional cerebral glucose metabolism and blood flow;rCBF). Furthermore, AD clinical disease progression despite brain clearance of A[unreadable] by immunization further underscores the importance of understanding the downstream consequences of A[unreadable] much earlier in the disease course when prevention and intervention strategies may be most effective. Molecular neuroimaging methods provide a unique opportunity to understand the downstream consequences of A[unreadable] in the course of MCI and the AD transition. Mechanistic hypotheses, based on data from human neuropathologic studies and transgenic mouse models, can be tested in the living human brain. A relationship between A[unreadable] deposition and downstream monoamine (MA) degeneration has been appreciated in several transgenic amyloid mouse models. Relative to other MA systems, 5-HT transporter and receptor alterations are a consistent finding in AD and have been suggested in MCI by recent neuroimaging studies, including the PI's preliminary data. A[unreadable] associated 5-HT degeneration may be an early neurobiological substrate of neuropsychiatric symptoms (NPS;depression, irritability, anxiety) that are common in MCI and are major predictors of further cognitive decline. 5-HT degeneration may be involved in the AD transition and may represent a promising therapeutic mechanism for multiple targets (e.g., A[unreadable], neuroprotection, cognitive and NPS). Thus, understanding the relationship between A[unreadable] and 5-HT degeneration in vivo has implications for identifying subjects at higher risk for disease progression and for informing the development of prevention and intervention strategies. The proposed study will evaluate multi-domain, amnestic MCI (mdMCI) and demographically matched control subjects concurrently with high resolution PET scanning, well-established radiotracers for (1) 5-HT transporter availability (SERT, [11C]-DASB) and (2) A[unreadable] ([11C]-PiB) and longitudinal clinical follow-up. The hypotheses will be tested that: Greater A[unreadable] and decreased SERT in similar regions, including anterior and posterior cingulate, superior and middle frontal cortices and precuneus will be observed in mdMCI compared to controls. The combination of SERT and A[unreadable] will be a better predictor of cognitive decline and worsening of NPS than either measure separately. The proposed studies will provide unique information regarding 5-HT degeneration and A[unreadable] relative to neurodegeneration (MR volumetric and PET rCBF changes) and symptomatology and the transition from mdMCI to AD. The data are a fundamental basis for longitudinal studies and for future studies to evaluate other aspects of A[unreadable] associated MA degeneration. PUBLIC HEALTH RELEVANCE: 2.3 million Individuals have been diagnosed with Alzheimer's Disease in the United States. The case burden is expected to quadruple in the next 50 years and the current cost to society has been estimated to be $100 billion dollars per year. The proposed study will provide an understanding of the early disease course that is critically needed to identify individuals at risk for progression and to develop safe and effective therapeutic targets for prevention and symptomatic treatment.